Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma.

PURPOSE KW-0761, a defucosylated humanized anti-CC chemokine receptor 4 (CCR4) antibody, exerts a strong antibody-dependent cellular cytotoxic effect. This phase I study assessed the safety, pharmacokinetics, recommended phase II dose and efficacy of KW-0761 in patients with relapsed CCR4-positive adult T-cell leukemia-lymphoma (ATL) or peripheral T-cell lymphoma (PTCL). PATIENTS AND METHODS Sixteen patients received KW-0761 once a week for 4 weeks by intravenous infusion. Doses were escalated, starting at 0.01, 0.1, 0.5, and finally 1.0 mg/kg by a 3 + 3 design. RESULTS Fifteen patients completed the protocol treatment. Only one patient, at the 1.0 mg/kg dose, developed grade 3 dose-limiting toxicities, skin rash, and febrile neutropenia, and grade 4 neutropenia. Other treatment-related grade 3 to 4 toxicities were lymphopenia (n = 10), neutropenia (n = 3), leukopenia (n = 2), herpes zoster (n = 1), and acute infusion reaction/cytokine release syndrome (n = 1). Neither the frequency nor severity of toxicities increased with dose escalation. The maximum tolerated dose was not reached. Therefore, the recommended phase II dose was determined to be 1.0 mg/kg. No patients had detectable levels of anti-KW-0761 antibody. The plasma maximum and trough, and the area under the curve of 0 to 7 days of KW-0761, tended to increase dose and frequency dependently. Five patients (31%; 95% CI, 11% to 59%) achieved objective responses: two complete (0.1; 1.0 mg/kg) and three partial (0.01; 2 at 1.0 mg/kg) responses. CONCLUSION KW-0761 was tolerated at all the dose levels tested, demonstrating potential efficacy against relapsed CCR4-positive ATL or PTCL. Subsequent phase II studies at the 1.0 mg/kg dose are thus warranted.

[1]  K. Yamaguchi,et al.  Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma: a proposal from an international consensus meeting. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  S. Iida,et al.  Defucosylated anti-CCR4 monoclonal antibody exercises potent ADCC-mediated antitumor effect in the novel tumor-bearing humanized NOD/Shi-scid, IL-2Rγnull mouse model , 2008, Cancer Immunology, Immunotherapy.

[3]  D. Weisenburger,et al.  International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  S. Iida,et al.  Augmentation of antitumour activity of defucosylated chimeric anti-CCR4 monoclonal antibody in SCID mouse model of adult T-cell leukaemia/lymphoma using G-CSF , 2008, British journal of haematology.

[5]  R. Ueda,et al.  VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  S. Iida,et al.  Defucosylated Anti–CC Chemokine Receptor 4 Monoclonal Antibody Combined with Immunomodulatory Cytokines: A Novel Immunotherapy for Aggressive/Refractory Mycosis Fungoides and Sézary Syndrome , 2007, Clinical Cancer Research.

[7]  D. Taub,et al.  Human Peripheral Blood T Regulatory Cells (Tregs), Functionally Primed CCR4+ Tregs and Unprimed CCR4− Tregs, Regulate Effector T Cells Using FasL1 , 2007, The Journal of Immunology.

[8]  Ryuzo Ueda,et al.  CCR4 as a novel molecular target for immunotherapy of cancer , 2006, Cancer science.

[9]  S. Iida,et al.  Non-fucosylated therapeutic antibodies as next-generation therapeutic antibodies , 2006, Expert opinion on biological therapy.

[10]  Shinji Hosoi,et al.  Comparison of cell lines for stable production of fucose‐negative antibodies with enhanced ADCC , 2006, Biotechnology and bioengineering.

[11]  S. Iida,et al.  Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege. , 2006, Cancer research.

[12]  A. López-Guillermo,et al.  CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. , 2006, The Lancet. Oncology.

[13]  W. Zou Regulatory T cells, tumour immunity and immunotherapy , 2006, Nature Reviews Immunology.

[14]  N. Schmitz,et al.  Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of t , 2005, Blood.

[15]  Weiping Zou,et al.  Immunosuppressive networks in the tumour environment and their therapeutic relevance , 2005, Nature Reviews Cancer.

[16]  K. Shitara,et al.  The CC Chemokine Receptor 4 as a Novel Specific Molecular Target for Immunotherapy in Adult T-Cell Leukemia/Lymphoma , 2004, Clinical Cancer Research.

[17]  T. Nomura,et al.  Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells. , 2004, International immunology.

[18]  S. Iida,et al.  CXC Chemokine Receptor 3 and CC Chemokine Receptor 4 Expression in T-Cell and NK-Cell Lymphomas with Special Reference to Clinicopathological Significance for Peripheral T-Cell Lymphoma, Unspecified , 2004, Clinical Cancer Research.

[19]  謙 大間知 CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma.Coiffier B,et al.N Engl J Med 2002;346(4):235-42--CHOP+リツキシマブ併用療法は、CHOP療法を上回る治療法であり、DLBCLの治療動向に大きなimpactを与えた , 2004 .

[20]  K. Shitara,et al.  Defucosylated Chimeric Anti-CC Chemokine Receptor 4 IgG1 with Enhanced Antibody-Dependent Cellular Cytotoxicity Shows Potent Therapeutic Activity to T-Cell Leukemia and Lymphoma , 2004, Cancer Research.

[21]  S. Iida,et al.  Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[22]  M. Matsuoka,et al.  Phase II Study of Cladribine (2-Chlorodeoxyadenosine) in Relapsed or Refractory Adult T-Cell Leukemia-Lymphoma , 2003, International journal of hematology.

[23]  M. Tomonaga,et al.  Deoxycoformycin-Containing Combination Chemotherapy for Adult T-Cell Leukemia-Lymphoma: Japan Clinical Oncology Group Study (JCOG9109) , 2003, International journal of hematology.

[24]  K. Shitara,et al.  The Absence of Fucose but Not the Presence of Galactose or Bisecting N-Acetylglucosamine of Human IgG1 Complex-type Oligosaccharides Shows the Critical Role of Enhancing Antibody-dependent Cellular Cytotoxicity* , 2003, The Journal of Biological Chemistry.

[25]  G. Pinkus,et al.  Increased CCR4 expression in cutaneous T cell lymphoma. , 2002, The Journal of investigative dermatology.

[26]  K. Matsushima,et al.  Frequent expression of CCR4 in adult T-cell leukemia and human T-cell leukemia virus type 1-transformed T cells. , 2002, Blood.

[27]  B. E. C. Oiffier,et al.  CHOP Chemotherapy plus Rituximab Compared with CHOP Alone in Elderly Patients with Diffuse Large-B-Cell Lymphoma , 2002 .

[28]  A. Iellem,et al.  Unique Chemotactic Response Profile and Specific Expression of Chemokine Receptors Ccr4 and Ccr8 by Cd4+Cd25+ Regulatory T Cells , 2001, The Journal of experimental medicine.

[29]  M. Duvic,et al.  Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  D. Dorfman,et al.  Expression pattern of T-cell-associated chemokine receptors and their chemokines correlates with specific subtypes of T-cell non-Hodgkin lymphoma. , 2000, Blood.

[31]  J. Armitage,et al.  Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  K. Matsushima,et al.  Selective recruitment of CCR4-bearing Th2 cells toward antigen-presenting cells by the CC chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine. , 1999, International immunology.

[33]  M. Narabayashi,et al.  Feasibility and pharmacokinetic study of a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) in relapsed B-cell lymphoma. The IDEC-C2B8 Study Group. , 1998, Annals of oncology : official journal of the European Society for Medical Oncology.

[34]  D. Maloney,et al.  IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  M. Grever,et al.  National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. , 1996, Blood.

[36]  R. Ohno,et al.  Treatment of adult T‐cell leukemia/lymphoma with MST‐16, a new oral antitumor drug and a derivative of bis(2,6‐dioxopiperazine) , 1993 .

[37]  M. Shimoyama,et al.  Diagnostic criteria and classification of clinical subtypes of adult T‐cell leukaemia‐lymphoma , 1991, British journal of haematology.

[38]  N. Kochibe,et al.  Systematic fractionation of oligosaccharides of human immunoglobulin G by serial affinity chromatography on immobilized lectin columns. , 1987, Analytical biochemistry.

[39]  A. Shimizu,et al.  Structural and numerical variations of the carbohydrate moiety of immunoglobulin G. , 1982, Journal of immunology.

[40]  T. Waldmann,et al.  Metabolic properties of IgG subclasses in man. , 1970, The Journal of clinical investigation.